CLINICAL INVESTIGATION Endogenous biosynthesis of prostacyclin during cardiac catheterization and angiography in man

The potent platelet inhibitory and vasodilator properties of prostacyclin suggest that levels of this substance may be of relevance to drug action and pathologic processes in the coronary vascular bed. Attempts to estimate the coronary secretion rate of prostacyclin have relied on measurements of metabolites obtained via cardiac catheter, usually as an adjunct to coronary angiography. To test the hypothesis that such procedures might themselves perturb endogenous biosynthesis of prostacyclin we used mass spectrometry to measure plasma levels of 6-keto-prostaglandin (PG) F,, across the coronary vascular bed, as well as to assess the excretion of a major urinary metabolite, 2,3-dinor-6keto-PGF,, (PGI-M), in patients undergoing cardiac catheterization. PGI-M excretion increased variably from a median 100 to 205 pg/mg creatinine (p < .01) during catheterization with angiography and remained elevated 2 to 4 hr after initiation of the procedure. However, cardiac catheterization without angiography also stimulated metabolite excretion, perhaps reflecting catheter-induced vascular trauma. The direct effect of radiocontrast media on vascular release of prostacyclin was indicated by increased PGI-M excretion in healthy volunteers administered intravenous radiocontrast and by studies of the canine coronary artery and jugular vein in vitro. Measurement of plasma 6-keto-PGF, after left heart catheterization showed that levels in aortic (21 +8 pg/ml) and coronary sinus (14 ± 2 pg/ml) blood were increased compared with peripheral venous levels (c 4 + 1 pg/ml) determined before this procedure. The aortic and coronary sinus concentrations of 6-keto-PGF,, both increased markedly in one of the five patients after injection of radiocontrast but an aortic coronary sinus gradient of 6-ketoPGF, was undetectable before or after angiography. These results indicate that cardiac catheterization and angiography are associated with an increase in prostacyclin formation in vivo. Circulation 71, No. 3, 434-440, 1985. CONSIDERABLE EVIDENCE implicates platelet activation in the events surrounding vascular occlusion of the coronary circulation. Both autopsy and angiographic investigations have demonstrated that occlusive thrombi usually accompany transmural myocardial infarction,' 2 and several reports suggest that this precedes rather than follows the ischemic episode. Studies of platelet function in acute myocardial infarction have demonstrated spontaneous platelet aggregaFrom the Divisions of Clinical Pharmacology and Cardiology. Vanderbilt University, Nashville. Supported by NIH grants HL 30400, GM 07569, GM 15431, and RR 00095 and by a grant from the Tennessee Affiliate of the American Heart Association. Dr. Roy was supported by a fellowship from the Quebec Heart Foundation. Dr. Knapp was supported in part by a grant from the Burroughs Wellcome Fund. Dr. Robertson is an Established Investigator of the American Heart Association. Dr. FitzGerald and Dr. Knapp are the recipients of Faculty Development Awards from the Pharmaceutical Manufacturer's Association Foundation. Address for correspondence: Dr. Garret A. FitzGerald. Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232. Received Feb. 27, 1984; revision accepted Nov. 21 1984. *Present address: L'Institut de Cardiologie de Quebec, 2725 Ch. Ste.-Foy, Quebec, Canada GIV-4G5. tion in vitro, abnormal disaggregation of platelets, increased circulating platelet aggregates, and increased levels of platelet secretory granule constituents in peripheral blood.'2 6Increased platelet aggregates also have been found in coronary sinus blood during transient ischemic episodes in patients with vasotonic angina.' More recently, attempts have been made to define the role of oxygenated metabolites of arachidonic acid in the mediation of such occlusive events in vivo. Thromboxane A2, the principle cyclooxygenase product of arachidonic acid in the platelet,9 is a potent vasoconstrictor and stimulus to platelet aggregation, whereas prostacyclin, the predominant product in vascular endothelium,'0 has opposite effects on both vascular tone and platelet function. It has been suggested that an "imbalance" in the production rates of these products might be of fundamental importance in the development of thrombotic occlusions of the coronary vascular bed in vivo' X and studies have been performed to obtain biochemical evidence of such a mechanism in CIRCULATION 434 by gest on M ay 8, 2017 http://ciajournals.org/ D ow nladed from PATHOPHYSIOLOGY AND NATURAL HISTORY-CARDIAC CATHETERIZATION man. Because of their evanescent nature, neither thromboxane A2 nor prostacyclin can be measured directly in the human circulation. Attempts to apply bioassay techniques ex vivo have proved to be insufficiently accurate for quantitative purposes,"2 so investigators have generally relied on measurements of stable, inactive metabolites of these compounds, most commonly thromboxane B213 14 and 6-keto-prostaglandin (PG) Fla' 15 Levels of these products in coronary sinus and aortic blood have been used to estimate arachidonic acid metabolism in the coronary bed in a variety of occlusive syndromes and to implicate prostacyclin biosynthesis in the mediation of beneficial drug action.'6 In the majority of such studies the samples used have been obtained via cardiac catheter, but if significant prostanoid formation occurs ex vivo or secondary to procedure-related artifacts in vivo, the data provided by this approach are of questionable value in assessing the roles of these compounds in coronary pathophysiology. To test the hypothesis that cardiac catheterization or angiography per se might alter endogenous prostanoid formation in man, we have determined the effects of these procedures on a noninvasive index of prostacyclin biosynthesis in vivo, namely the excretion of 2,3-dinor-6-keto-PGFia (PGI-M), a major urinary metabolite of prostacyclin in man, and compared the levels of 6-keto-PGF,a, the hydration product of prostacyclin, in peripheral plasma with those in the coronary circulation after cardiac catheterization. In addition, we have assessed the possibility of a direct stimulating effect of radiocontrast media on arterial 6-keto-PGF a formation in vitro.